Abstract 12156: Chronic Nuclear Acidosis Defines Aging and Lifespan by Histone 4 Lysine 5 Acetylation in Mice
Backgrounds: A transient low pH stressor gives great impacts to the nucleus such as histone and DNA modulation, but little is known about whether and how chronic pH stressor affects aging and lifespan. We recently identified coupling factor 6 (CF6) induces long-term low pH in the cells by enhanced proton import through ecto-F1Fo complex and by reduced proton export through inhibition of Na+-K+ ATPase. Using CF6 overexpressing transgenic mice (TG), we analyzed how CF6 affects aging.
Methods and Results: TG (n=20) manifested early senescence-associated phenotypes such as signs of hair graying and sparseness, resulting in shortened lifespan compared with wild-type mice (WT, n=13) (median values; 108±2 vs 131±11 weeks, p<0.05). Long-term low pH disturbed nuclear envelope protein lamin A/C and emerin without affecting BAF as the lamina components. These changes were concomitant with the decrease in nucleoplasmic HDAC3 as a binding partner of emerin and in class IIa HDAC4 which recruits HDAC3 to their substrates in the nucleus. In TG cells and CF6-treated cells, the nuclear-shape deformity and the decrease in heterochromatin were observed, and epigenetic changes in histone 4 lysine 5 (H4K5) acetylation was induced by down-regulation of HDAC3. Aging-associated markers of H3K4 and H4K20 trimethylation, caused by decreased each demethylase, were also increased in TG cells. Autophagy-related Atg7 was commonly decreased in various TG tissues, and deletion of the Atg7 promoter region at -800 through -400 increased luciferase activity. ChIP assay revealed that PCR in the region of Atg7 promoter at -441 through -763 was increased by CF6 after immuneprecipitate with anti-acetyl H4K5 antibody but not with anti-trimethyl histone H3K4 or H4K20 antibody. Collectively, the region where H4K5 was acetylated by chronic nuclear acidosis is repressive to Atg7 expression, leading to impaired autophagy and aging. Another long-term low pH caused by salt loading, which reduces proton export by Na+-K+-ATPase inhibition, showed a similar phenotype in mice.
Conclusions: Acquired laminopathy by long-term low nuclear pH switched on aging by epigenetic mechanisms. These findings shed light on aging mechanism, and may provide a novel target for anti-aging therapy.
Author Disclosures: T. Osanai: None. K. Izumiyama: None. M. Tanaka: None. K. Murakami: None. T. Kinjo: None. T. Tanno: None. H. Tomita: None. A. Kobayashi: None. K. Okumura: None.
- © 2014 by American Heart Association, Inc.